Neurostimulator with activation based on changes in body temperature

ABSTRACT

Improved methods and devices are provided for detecting and/or predicting the onset of an undesirable physiological event or neural state, such as an epileptic seizure, to facilitate rapid intervention with a treatment therapy such as neurostimulation or drug therapy. The methods and devices involve monitoring the patient&#39;s body temperature, preferably by an implanted temperature sensor, to detect a sudden change in a body temperature parameter. The temperature parameter change may comprise an increase or decrease in the patient&#39;s body temperature, time rate of change of body temperature, or a difference in a moving average temperature for a first period from that of a second period. When a parameter change is detected that exceeds a threshold, neurostimulation therapy is delivered to a neural structure of the patient.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to implantable medical devices, andmore particularly to medical devices that may be activated or adapted toone or more physiological conditions in a patient in which the devicesare implanted.

2. Background

There have been many improvements over the last several decades inmedical treatments for disorders of the nervous system, includingepilepsy and other motor disorders, and conditions caused by orinvolving abnormal neural discharge. One of the more recently availabletreatments involves applying an electrical signal to reduce symptoms oreffects of such neural disorders. For example, electrical signals havebeen successfully applied to neural tissue in the human body to providevarious benefits, including reducing occurrences of seizures and/orimproving or ameliorating other conditions such as depression. Aparticular example of such a treatment regimen involves applying anelectrical signal to the vagus nerve of the human body to reduce oreliminate epileptic seizures, as described in U.S. Pat. No. 4,702,254 toDr. Jacob Zabara, which is hereby incorporated by reference in itsentirety in this specification.

Electrical stimulation of the vagus nerve may be provided by implantingan electrical device underneath the skin of a patient, detecting asymptom or effect associated with the condition, and deliveringelectrical stimulation pulses to the vagus nerve. Alternatively, thesystem may operate without a detection system if the patient has beendiagnosed with epilepsy, and the device may simply apply a series ofelectrical pulses to the vagus nerve (or another cranial nerve)intermittently throughout the day, or over another predetermined timeinterval. Stimulation that involves a detection and/or sensing operationis referred to as active stimulation, while stimulation without adetection or sensing operation is known as passive stimulation.

Many implantable pulse generators used for electrical stimulation ofneurological tissue operate according to a therapy algorithm programmedinto the device by a health care provider such as a physician. One ormore parameters of the therapy (e.g., current amplitude, pulse width,pulse frequency, and on-time and off-time) may thereafter be changed byreprogramming the neurostimulator after implantation by transcutaneouscommunication between an external programming device and the implantedneurostimulator. The ability to program (and later re-program) theimplanted device permits a health care provider to customize thestimulation therapy to the patient's needs, and to update the therapyperiodically should those needs change.

It is desirable, however, for an implantable medical device, such as aneurostimulator, to be able to provide active stimulation byautomatically detecting one or more physiological parameters andresponsively initiating a stimulation therapy specifically tailored tothe physiological parameters detected, without the necessity ofintervention by a health care provider. The detected parameterspreferably indicate the onset or potential onset of an undesirablephysiological event, such as an epileptic seizure. Detection of suchphysiological events is, however, complicated by physiologicaldifferences among patients.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides improved methods ofdetecting and/or predicting the onset of an undesirable physiologicalevent or neural state, such as an epileptic seizure, in order tofacilitate rapid intervention with a treatment therapy such asneurostimulation or drug therapy. In many instances, the temperature ofa patient undergoing a physiological event such as an epileptic seizureundergoes a sudden, rapid fluctuation up or down shortly before orcontemporaneous with seizure onset. In one embodiment, the inventioncomprises monitoring the patient's body temperature, preferably by animplanted temperature sensor, to detect a rapid change in a bodytemperature parameter that is incompatible with physical exercise ornormal physiological conditions. The temperature parameter change maycomprise an increase or decrease in the patient's body temperature, atime rate of change of body temperature exceeding a threshold level, ora difference in a moving average temperature for a first period fromthat of a second period.

The invention also provides methods of providing electricalneurostimulation therapy to treat an undesirable physiological event orneural state by responding to a detected temperature parameter change byinitiating or altering a therapy regimen. In a preferred embodiment theresponsive treatment comprises a neurostimulation therapy, morepreferably electrical stimulation of a cranial nerve, and mostpreferably electrical stimulation of the vagus nerve. In one embodiment,the responsive treatment comprises initiating vagus nerve stimulation(VNS) according to programmed stimulation parameters. In an alternativeembodiment, the responsive treatment comprises changing one or moreparameters of an existing VNS regimen already implemented. Theresponsive treatment may, in a different embodiment, comprise initiatingelectrical stimulation to a trigeminal and/or a glossopharyngeal nerveof the patient rather than (or in addition to) the vagus nerve. In astill further embodiment, the responsive treatment comprises providing adrug therapy from a drug pump coupled to the patient's body.

To provide a more efficacious temperature detection algorithm for thepatient that reduces the likelihood of a false positive indication, thepatient may be tested by one or more exercise, physiological orenvironmental tests to determine a maximum rate of temperature changeassociated with exercise or other physiological conditions (e.g., arapid change in environmental temperature such as emerging from atemperature-controlled building into extremely hot or cold outsideconditions). The maximum (and/or minimum) temperature, rate oftemperature changes, moving average temperatures, and/or othertemperature parameters occurring during the tests may be recorded andused in methods and devices of the present invention to ensure that thetemperature parameter change detected and used to triggerneurostimulation is beyond a threshold value, which may correspond tonormal physiological changes for the patient.

The precise mechanism for the temperature fluctuations that may functionas a precursor of an epileptic seizure is not fully understood atpresent. Without being bound by theory, it is believed that such changesmay arise from an instability of autonomic tone caused by electricalactivity associated with a seizure. There is, however, uncertainty as tothe relative contributions of the sympathetic and parasympatheticnervous system influences on autonomic tone. It is also possible that aninstability of autonomic tone and temperature instability precedechanges in the patient's electroencephalogram (EEG) readings or otherphysical manifestations of seizure activity, such as uncontrollableviolent movements. In any case, if the responsive treatment can beimplemented sooner, there will be a greater likelihood that the seizure(or other undesired physiological event or neural state) can beinhibited altogether, terminated sooner, or reduced in either severityor duration.

In another aspect, the present invention provides a neurostimulatorsystem comprising a pulse generator capable of generating an electricalpulse to stimulate a neural structure (such as a cranial nerve) in apatient, a stimulation electrode assembly, and at least one temperaturesensor element. The temperature sensor element may be considered as partof a temperature sensing unit that is, in turn, part of a controller forregulating how the neurostimulation therapy is applied to the neuralstructure.

The temperature sensing unit measures and analyzes body temperature toderive temperature parameters that may be used to initiate or alter aneurostimulation therapy when a temperature parameter exceeds athreshold value. The temperature parameters may include bodytemperature, rate of change of body temperature, or differences inmoving average body temperatures over different time domains orintervals. In addition to the temperature sensing element, thetemperature sensing unit preferably comprises timing circuitry forcontrolling the sampling rate at which temperature is sensed with thesensor element, temperature analysis circuitry for calculatingtemperature parameters and/or analyzing a temperature data stream fromthe temperature sensor element(s), and activation circuitry forinitiating or altering a neurostimulation therapy. The controller isalso preferably comprises a memory element for storing temperature datafrom the temperature sensing unit.

The temperature sensor element may comprise any of a number of differenttypes of sensors, so long as it is capable of sensing temperature whenimplanted in the body of the patient. In one embodiment the sensorelement comprises a silicon-based temperature sensor integrated into amicroprocessor or other integrated circuit. In another embodiment, thetemperature sensor may comprise an electrode or thermocouple coupled tothe distal end of a lead whose proximal end is coupled to the pulsegenerator. In any event, the temperature sensor element is coupled tothe pulse generator and senses a body temperature of the patient.

In preferred embodiments, the pulse generator comprises a biocompatiblecase enclosing and protecting a battery and the internal pulsegeneration circuitry such as the controller. In preferred embodiments,the pulse generator, stimulation electrode assembly, and controller(including the temperature sensing unit) are all implantable. Inalternative embodiments, one or more of the components of the system maybe external.

In a particular embodiment of the neurostimulation system, a temperaturesensor provides a time series data stream of body temperaturemeasurements for the patient, which is stored in a memory. Thecontroller may be programmed to sample the temperature at a desiredinterval ranging from 0.01 seconds to one hour or more. In preferredembodiments, the temperature is measured at intervals from 0.5 secondsto 1 hour, and more preferably from 1 second to 30 minutes. Temperatureanalysis circuitry analyzes the temperature data stream to measure orcalculate and store various temperature parameters, including bodytemperature, running averages of body temperature, and rates of changeof body temperature over several time period domains that may range fromone second to one hour or more. These time domains may comprise, withoutlimitation, 1 second, 10 seconds, 15 seconds, 30 seconds, 1 minute, 2minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours,3 hours, 6 hours, and 24 hours.

In one embodiment, the temperature analysis circuitry determines andmaintains a log of the minimum and maximum temperatures, running averagetemperatures, and rates of change of temperature over one or more timedomains. Because individual temperature measurements may be highlyvariable, calculations of time rate of change of temperature may bebased on moving averages rather than individual temperature readings.For example, a time rate of change for a 1 minute temperature domain maybe calculated by comparing a moving average for a five second periodwith the five second moving average for the time period exactly oneminute prior to the first moving average. Similarly, a five minute timerate of change may be calculated by subtracting a moving average of a 1second domain from a second 1 second moving average for a period exactlyfive minutes later and dividing the difference by five. Alternatively,individual temperature readings instead of moving averages may be usedto calculate time rates of temperature change.

The temperature analysis circuitry may also calculate and compareshorter term running average temperatures (e.g., 10 seconds, 30 seconds)to longer term running averages (e.g., 10 minutes, 30 minutes, 1 hour).For example, a short term running average temperature for the previous 1minute time domain may be continuously compared with a longer termrunning average for the past 10 minutes, and the difference may bestored.

One or more of temperature, time rate of change of temperature, orchanges in running average temperature may be compared to thresholds oftemperature, rate of change of temperature, or differences in runningaverage temperature to provide an indication of the occurrence of anundesirable physiological event or neural state, such as onset of anepileptic seizure. The programmed threshold for temperature may be setat a temperature above normal body temperature or a higher temperatureabove a body temperature associated with exercise. In anotherembodiment, a temperature drop of even slightly below normal bodytemperature may be taken to indicate an undesirable medical condition.The threshold for time rate of change of temperature is preferably setat a rate that exceeds the rate of temperature change during periods ofintense exercise. A negative threshold may also be set at a temperaturedrop exceeding that of moving from a warm environment to an extremelycold environment.

Changes in moving average temperatures may be compared to screen outchanges associated with exercise periods and moving from a warm to acold environment. These thresholds may be set at a slope or graderepresentative of, for example, an increase or decrease in absolutetemperature exceeding 1° F. within 3 minutes or less. The foregoingexamples are provided as nonlimiting examples only. In a preferredembodiment, the patient may be tested by monitoring body temperatureafter the device is implanted during several periods of exercise forshort periods of time. In this manner maximum temperature parameters fornormal physiological conditions may be easily determined and thethresholds programmed on an individual basis.

Once temperature parameter thresholds are established, parametersexceeding these thresholds may be detected by the temperature analysiscircuit in conjunction with the temperature sensor. The temperatureanalysis circuitry preferably generates a therapy initiation signal andsends the signal to the activation circuitry for initiating or alteringa neurostimulation therapy. In one embodiment, the signal simply causesthe activation circuitry to activate the neurostimulation therapyaccording to the existing programming. In another embodiment, theactivation circuitry alters the therapy by increasing or decreasing oneor more stimulation parameters for a predefined period of time, such aschanging the duty cycle from a stimulation on-time of 30 seconds to astimulation on-time of 300 seconds for a period of thirty minutes, afterwhich the on-time would be restored to 30 seconds. In a differentembodiment, the activation circuitry alters the therapy by increasingthe stimulation current by 0.5 milliamps for a similar time periodbefore returning to the prior setting. It is believed that such atherapy initiation circuit, when implemented in a vagus nerve stimulatorsystem, may inhibit, abort, or alleviate an epileptic seizure or otherundesired physiological event.

Cranial nerve stimulation therapy is not harmful to the patient even ifthe therapy initiation signal is a false indication of the presence ofan undesirable medical condition. Accordingly, the device may also beprogrammed to initiate or alter neurostimulation therapy whenever one ormore temperature parameters exceeds a threshold that may be consistentwith an undesirable medical condition, without regard to whether or notthe change may also be consistent with normal physiological activity. Inthis instance, temperature parameter thresholds may be established by atraining protocol designed to determine temperature parameterfluctuations that may indicate an undesirable medical condition. Theimplantable neurostimulator may provide such a trained response byimplementing a method that comprises sensing temperature with thetemperature sensor, generating a time series of signals representativeof the body temperature of the patient, and storing the time seriestemperature data stream in a memory. The method further comprisesdetermining when an undesired physiological event has occurred in apatient, and providing an indication of the occurrence of the event tothe controller. In response to the indication of the physiologicalevent, the temperature analysis circuitry analyzes the stored timeseries temperature data stream for a predetermined time intervalpreceding (and possibly after) the event to determine temperatureextrema, rates of temperature change, and differences in time weightedmoving averages within that period, as one or more markers to predictthe undesired physiological event (e.g., an epileptic seizure). Themethod also comprises continuing to monitor the temperature data streamfor the presence of the marker(s) and, if one or more marker is presentin the continuing data stream, initiating or altering theneurostimulation.

In another embodiment, the invention comprises a method of detecting andproviding therapy for an undesired physiological event such as anepileptic seizure. The method comprises using a temperature sensingelement to generate a time series of patient body temperaturemeasurements, analyzing the time series of patient body temperaturemeasurements to determine at least one temperature parameter, anddelivering electrical stimulation pulses to a cranial nerve when achange in the at least one temperature parameter exceeds a predeterminedthreshold change value. The time series of body temperature measurementsmay be stored in a memory element to facilitate the analysis of thedata. The temperature parameter change may comprise an increase ordecrease in the patient's body temperature, a time rate of change ofbody temperature over a first time domain, or a difference in a movingaverage temperature for a first period from that of a second period. Thesensing element may comprise a temperature sensor incorporated into amicroprocessor. The threshold value may comprise a value associated withthe undesired physiological event.

In another embodiment, the invention comprises a method of detecting andproviding therapy for an undesired physiological event indicated by atemperature marker. The method comprises sensing body temperature of apatient in a first temperature sensing step, generating a first timeseries temperature data stream for the patient, and storing the datastream in a memory. The method further comprises determining when anundesired physiological event has occurred, providing an indication ofthe occurrence of the undesired physiological event, and analyzing thetime series temperature data stream for a predetermined time intervalpreceding said event to determine at least one temperature marker in thedata stream associated with the event. Following determination of thetemperature marker, the method comprises sensing body temperature of apatient in a second sensing step, generating a second time seriestemperature data stream for the patient, optionally storing the secondtime series data stream in a memory, and analyzing the second timeseries temperature data stream for the presence of the temperaturemarker. Finally, the method comprises initiating or altering aneurostimulation therapy in response to the detection of the temperaturemarker in the second time series data stream.

In another embodiment, the use of extra-physiologic changes intemperature parameters to detect an undesired physiological event may beaugmented by one or more sensors for a different physiological parameterthat is likewise subject to rapid fluctuation preceding or coincidentwith the occurrence of the undesired physiological event. In thisembodiment, the invention provides an implantable neurostimulatorcomprising a pulse generator, a stimulation electrode assembly, aplurality of sensors coupled to the pulse generator, and a controller.The plurality of sensors are capable of sensing at least twophysiological parameters selected from the group consisting of atemperature parameter, an action potential in a nerve tissue, a heartparameter, a blood parameter, and brain wave activity. In a preferredembodiment, at least one of the plurality of sensors comprises atemperature sensor for sensing body temperature of the patient andgenerating a time series of temperature data. The controller receivesand analyzes the sensor signals from the plurality of sensors; and thepulse generator initiates or changes a neurostimulation therapy regimenin response to the controller's analysis.

The device may additionally be programmed to apply a periodicprophylactic stimulation of the nerve or nerve bundle to modulate itselectrical activity in an appropriate manner for inhibiting seizuresregardless of whether or not an excessive temperature change isdetected.

Accordingly, it is a more specific aim of the present invention toprovide methods and apparatus for automatically and selectivelymodulating the electrical activity of a cranial nerve, preferably thevagus nerve, in a predetermined manner in response to detection of asudden change in a temperature parameter of the patient's body, toinhibit, abort or alleviate an undesirable physiological event.Detection of such a change of a temperature parameter offers relativeease of detection, reliability as an indicator, and simplicity of thesensor and implant procedure.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIG. 1 is a stylized diagram of a prior art implantable medical devicesuitable for use in stimulating a vagus nerve of a patient, depicted asimplanted into a patient's body and showing an external programmingsystem;

FIG. 2 is a stylized diagram of an embodiment of an implantable medicaldevice suitable for use in the present invention, with a temperaturesensor integrally coupled to a pulse generator case;

FIG. 3 is a stylized diagram of another embodiment of an implantablemedical device suitable for use in the present invention, with atemperature sensor at the distal end of a lead coupled to a pulsegenerator;

FIG. 4 is a block diagram of an implantable pulse generator inaccordance with one illustrative embodiment of the present invention;

FIG. 5 illustrates an implantable pulse generator suitable for use inthe present invention, showing the header and electrical connectors forcoupling the device to a lead/electrode assembly;

FIG. 6 shows a lead and electrodes suitable for use in the presentinvention attached to a vagus nerve of a patient.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the invention to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the invention as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the invention are described herein. In theinterest of clarity, not all features of an actual implementation aredescribed in this specification. In the development of any such actualembodiment, numerous implementation-specific decisions must be made toachieve the design-specific goals, which will vary from oneimplementation to another. It will be appreciated that such adevelopment effort, while possibly complex and time-consuming, wouldnevertheless be a routine undertaking for persons of ordinary skill inthe art having the benefit of this disclosure.

The particular embodiments disclosed above are illustrative only, as theinvention may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown, other than as describedin the claims below. The particular embodiments disclosed above may bealtered or modified and all such variations are considered within thescope and spirit of the invention. Accordingly, the protection soughtherein is as set forth in the claims below.

FIG. 1 illustrates a prior art neurostimulation system for stimulationof the vagus nerve 100 of a patient. Pulse generator 10 is provided witha main body 30 comprising a case or shell 27 (FIG. 1) with a header 40having one or more connectors 50 (FIG. 5) for connecting to leads 60.The generator 10 is implanted in the patient's chest in a pocket orcavity formed by the implanting surgeon below the skin (indicated by adotted line 90), similar to the implantation procedure for a pacemakerpulse generator. A stimulating nerve electrode assembly 70, preferablycomprising an electrode pair 72, 74, is conductively connected to thedistal end of an insulated electrically conductive lead assembly 60,which preferably comprises a pair of lead wires (one wire for eachelectrode of an electrode pair). Each lead wire in lead assembly 60 isattached at its proximal end to a connector 50 on case 27. The electrodeassembly 70 is surgically coupled to a vagus nerve 100 in the patient'sneck.

The electrode assembly 70 preferably comprises a bipolar stimulatingelectrode pair (FIG. 6), such as the electrode pair described in U.S.Pat. No. 4,573,481 issued Mar. 4, 1986 to Bullara. Persons of skill inthe art will appreciate that many electrode designs could be used in thepresent invention. The two electrodes are preferably wrapped about thevagus nerve, and the electrode assembly 70 is preferably secured to thenerve 100 by a spiral anchoring tether 76 (FIG. 6) such as thatdisclosed in U.S. Pat. No. 4,979,511 issued Dec. 25, 1990 to Reese S.Terry, Jr. and assigned to the same assignee as the instant application.Lead assembly 60 is secured, while retaining the ability to flex withmovement of the chest and neck, by a suture connection 80 to nearbytissue.

In one embodiment, the open helical design of the electrode assembly 70(described in detail in the above-cited Bullara patent), which isself-sizing and flexible, minimizes mechanical trauma to the nerve andallows body fluid interchange with the nerve. The electrode assembly 70preferably conforms to the shape of the nerve, providing a lowstimulation threshold by allowing a large stimulation contact area withthe nerve. In one embodiment, the electrode assembly 70 comprises twoelectrode ribbons (not shown), of a conductive material such asplatinum, iridium, platinum-iridium alloys, and/or oxides of theforegoing. The electrode ribbons preferably are individually bonded toan inside surface of an elastomeric body portion of the two spiralelectrodes 72 and 74 (FIG. 6), which may comprise two spiral loops of athree-loop helical assembly.

The lead assembly 60 may comprise two distinct lead wires or a coaxialcable whose two conductive elements are respectively coupled to one ofthe conductive electrode ribbons 72 and 74. One suitable method ofcoupling the lead wires or cable to the electrodes comprises a spacerassembly such as that disclosed in U.S. Pat. No. 5,531,778, althoughother known coupling techniques may be used. The elastomeric bodyportion of each loop is preferably composed of silicone rubber, and thethird loop 76 (which typically has no electrode) acts as the anchoringtether for the electrode assembly 70.

Referring to FIG. 4, distinct from the prior art, the pulse generator 10of a preferred embodiment of the invention includes a controller 12comprising a temperature sensing unit 14 for measuring the bodytemperature of a patient at predetermined or programmable intervals. TheTSU 14 includes a temperature sensor element 16 such as a thermocouple,electrode, or a temperature sensor included as part of a microprocessor26 or integrated circuit, timing circuitry 18 for controlling the rateat which temperature measurements are taken, and analysis circuitry 20for calculating a number of temperature parameters such as time-weightedmoving average temperatures and time rates of change of temperature. TheTSU 14 may also include activation 22 circuitry for deciding when totrigger a stimulation burst from the pulse generator 10. Finally, amemory element 24 is used in conjunction with (or as part of) TSU 14 forstoring measured and calculated temperature data.

It will be appreciated by persons of skill in the art that one or moreof the components of TSU 14 as depicted in FIG. 4 may be depictedinstead as other parts of the controller 12, or as other blocks withinthe stimulator 10, without lack of accuracy. For example, the timingcircuitry and even the sensor element itself may be part of themicroprocessor 26, and the 14 element may comprise a RAM or other memorydevice known in the art. In addition, certain aspects of the inventionmay be implemented as hardware, firmware, software or combinationsthereof. Persons of skill in the art will understand that circuit layoutand hardware/firmware/software implementation decisions include numerousdesign choice issues, and unless specifically noted all such designsshould be considered as falling within the scope and spirit of theinvention.

In certain embodiments of the invention, the temperature sensor element16, such as sensor 110 (FIG. 2) may be provided integrally with case 27for sensing temperature under the control of the timing circuitry 18.Pulse generator 10 is typically implanted in the patient's body with afirst side facing the patient's skin and a second side facing theinterior of the patient's body. Because the purpose of the sensorelement 1 10 is to accurately measure the patient's core temperature, itis preferably located on the second side of pulse generator 10—facingthe interior of the patient's body—to avoid temperature gradientsinduced from outside the patient's body.

In another embodiment, the temperature sensor element may comprise athermocouple 140 at the distal end of a lead wire 130 coupled to aconnector 50 on the pulse generator 10, as shown in FIG. 3.Alternatively, the thermocouple may be present at the distal end of arigid member coupled to the pulse generator (not shown). More generally,by placing the sensor element at the distal end of a conducting andspacing element, a more reliable indication of core body temperature maybe obtained by locating the sensor element deeper insider the patient'sbody, thereby minimizing or removing altogether temperature effects fromthe exterior environment.

In a preferred embodiment, the temperature sensor element 16 comprises asilicon-based sensor element, preferably included as part of amicroprocessor 26 or ASIC chip. Such a sensor element reduces the numberof system components and consequently avoiding failure modes, such asfatigue-induced failure of a lead wire, associated with sensor elementsspaced remotely from the pulse generator 10. In addition, by includingthe sensor element as part of an integrated circuit chip within thepulse generator case 27, the sensor element 16 is protected from theharsh environment of the patient's body, contributing to potentiallylonger life of the sensor element 16 and avoiding premature failure.Moreover, one or more of the other elements of the temperature sensingunit 14, i.e., the timing circuitry 18, the analysis circuitry 20,activation circuitry 22, and memory element 24, may also be included aspart of the same microprocessor 26 or ASIC chip.

A view of the first side 29 (i.e., the side facing the skin of thepatient) of an implantable pulse generator 10 according to certainembodiments of the invention is illustrated in FIG. 5. The generator 10comprises a header 40 equipped with at least two connector sockets forcoupling an electrode assembly 70 and a temperature sensing element 16to connectors 50 on the pulse generator. In the embodiment of FIG. 5,the electrode assembly 70 is coupled to a coaxial-type cable lead 60that is connected to single connector socket having two connectors 50. Asecond connector socket is provided for connecting the proximal end of asecond coaxial lead 130 to a pair of connectors 50, with the distal endof lead 130 being coupled in turn to a thermocouple 140 or othertemperature probe, as shown in FIG. 3. In other embodiments, thetemperature sensor element 16 is provided as part of a microprocessor 26or ASIC chip located inside case 27 of pulse generator 10, and one ortwo connector sockets are provided in header 40 solely for connection tostimulation leads 60 (either a single coaxial socket or dual single-wiresockets).

In fully implantable embodiments, the invention provides activestimulation by sensing temperature parameters that may be associatedwith an undesired physiological event, such as an epileptic seizure, andautomatically initiating or adjusting cranial nerve stimulation therapyin response. In preferred embodiments, the TSU 14 is able tospecifically detect temperature parameters outside of the patient'snormal physiologic temperature parameters, and automatically initiatetherapy when it is determined that a change in the temperature parameteris likely to be associated with an undesired physiological event. Theparameters may comprise body temperature, rate of change of temperature,and moving average temperature differences.

Referring again to FIG. 4, in a particular embodiment of theneurostimulation system, a temperature sensor element 16 provides a timeseries data stream of body temperature measurement signals 150. Thesampling rate of the time series data stream is controlled by timingcircuitry 18, which preferably comprises registers allowing the samplingrate to be programmed by a user with external programming computer 160and handheld programming wand 170. The data is preferably converted fromanalog to digital data by conventional digital-to-analog circuitry (notshown) and stored in memory element 24 for analysis by analysiscircuitry 20. Alternatively, the temperate signal data stream may firstbe processed by analysis circuitry 20 (which in the alternativeembodiment preferably comprises temporary memory storage capacity) andused to calculate one or more temperature parameters. The digital data,including both the temperature measurements and the calculatedparameters, such as moving average temperatures and rates of change oftemperature, are then stored in memory element 24.

The timing circuitry 18 preferably allows the temperature sampling rateto be programmed over a wide range of sampling rates, including ratesranging from more than 100 temperature measurements per second to lessthan 1 temperature measurement per hour. Although more preciseindications of the occurrence of an undesired physiological event may beobtained at higher sampling rates, higher sampling rates require muchhigher power consumption and consequently significantly reduce batterylife for a fully implantable system. Accordingly, sampling rates on theorder of 1 second to 1 hour are most preferred. Extremely low samplingrates, such as one measurement each 30 minutes or hour, do not provideenough data to allow rapid temperatures to be detected, and thus areless preferred.

Temperature analysis circuitry 20 provides a desirable feature of thepresent invention. In particular, the circuitry determines one or moretemperature parameters and compares those parameters to thresholdvalues. If a parameter exceeds its threshold value, which indicates thatan undesired physiological event may have occurred or may soon occur,cause controller 12 to generate stimulation signals for delivery toelectrodes 72, 74 for stimulation of a cranial nerve.

In one embodiment, the temperature analysis circuitry 20 maintains a logof all temperature measurements for a predetermined log period, such as24 hours, and also calculates and stores minimum and maximumtemperatures, running average temperatures, and rates of change oftemperature for several shorter time domains within the log period. As anonlimiting example, for a system in which timing circuitry 18 providesa one minute sampling rate, analysis circuitry 20 may maintain a log ofstored body temperature readings for the previous 1 hour, and maycalculate and store rates of temperature change for the previous twominute, three minute and five minute periods based on the temperaturereadings for the most recent five minute period. If the temperaturechange for the previous two minute period exceeds 1° F., or the previousfive minute change exceeds 1.5° F., the activation circuitry mayinitiate stimulation of a vagus nerve of the patient. In addition, theanalysis circuitry 20 may calculate a two minute, five minute, and tenminute running average body temperature reading for the most recent tenminute period. If the moving average temperature for the previous twominute period differs from that of either the five or ten minute movingaverage temperatures by more than 0.5° F., the activation circuitry maylikewise initiate stimulation of a vagus nerve of the patient. It isunderstood that the time domains and temperature changes provided in theprevious examples are exemplary only, and other time domains andtemperature changes are within the scope of the invention.

In certain embodiments of the invention, maximum physiologicaltemperature changes, rates of temperature change, and changes betweenmoving average temperatures may be determined empirically for a patientby exercise tests after the neurostimulation system has been implantedin the body of the patient. For example, the patient may perform variousexercise tasks, and the effects of the exercise tasks on the foregoingtemperature parameters noted and stored by the temperature sensing unit14. If, for example, the patient's temperature rises by 2.0° F. over afive minute period, a rate of temperature change exceeding 0.4°F./minute can be used as a threshold above which any rate change willtrigger or alter (e.g., by extending the duration of) a neurostimulationtherapy. Whether determined empirically or otherwise, temperatureparameter thresholds are preferably set at a rate that exceeds the rateof temperature change during periods of intense exercise and ratesassociated with extreme environmental temperature differences.

False positive detections can be reduced by using a plurality oftemperature parameter changes in excess of a threshold level, ratherthan a single temperature parameter. For example, TSU 14 can beprogrammed such that the analysis circuitry 20 will only initiatestimulation if two temperature parameters exceed a threshold level. In aspecific example, the analysis circuitry 22 could require that thecurrent temperature exceed 100° F. and that the rate of temperaturechange for the most recent five minutes exceed 0.5° F./minute beforegenerating a therapy initiation signal and transmitting it to theactivation circuitry 22. In a different embodiment, the analysiscircuitry may require that the rate of temperature change for thepreceding three minute interval exceed 0.2° F./minute and that themoving average temperature for the preceding two minutes exceed themoving average for the preceding 10 minutes by 1.0° F. before therapy isinitiated.

The use of two or more temperature parameters to trigger therapy must bebalance against the fact that failure to detect an imminent undesiredphysiological event such as an epileptic seizure results in a missedopportunity to abort the seizure. In general, the failure to abort aseizure is a worse therapeutic outcome than neural stimulation inresponse to false positives, because the latter is not likely to produceharmful side effects.

On the other hand, an overly high sensitivity can result in continuousor nearly continuous therapy, which is not desirable. Preferably, thetime interval between consecutive applications of nerve stimuli shouldbe programmed to assure that a suitable minimum off time is provided toprevent overstimulation of a neural structure.

Although a preferred embodiment and method have been described herein,it will be apparent to persons skilled in the art of the invention, froma consideration of the foregoing disclosure, that variations andmodifications of the disclosed embodiment and method may be made withoutdeparting from the spirit and scope of the invention. Accordingly, it isintended that the invention shall be limited only to the extent requiredby the appended claims and the rules and principles of applicable law.

1. A method of providing electrical neurostimulation therapy to acranial nerve of a patient comprising: generating a time series oftemperature data representative of the body temperature of the patient;determining a time rate of change of body temperature for the patientover at least one predetermined time period; comparing the time rate ofchange of the patient's temperature with a threshold time rate of changeof temperature; and providing an electrical neurostimulation therapy toa cranial nerve of the patient if the time rate of change of thepatient's body temperature exceeds said threshold time rate of change.2. The method of claim 1, wherein said cranial nerve is selected fromthe group consisting of a vagus nerve, a trigeminal nerve, or aglossopharyngeal nerve.
 3. The method of claim 1 wherein said step ofproviding an electrical neurostimulation therapy comprises changing aparameter of a neurostimulation therapy selected from the groupconsisting of current amplitude, a cycle on-time and a cycle off-time.4. The method of claim 3 wherein said step of changing a parametercomprises increasing the current amplitude.
 5. The method of claim 3wherein said step of changing a parameter comprises increasing the cycleon-time.
 6. The method of claim 1 wherein said at least onepredetermined time period comprises a time period within the range of 15seconds to 24 hours.
 7. The method of claim 1 wherein said step ofgenerating a time series of temperature data comprises sensing bodytemperature of the patient with an implanted temperature sensor.
 8. Themethod of claim 7 further comprising the step of storing said timeseries temperature data in a memory.
 9. The method of claim 7 whereinsaid step of determining a time rate of change of body temperature forthe patient comprises determining a time rate of change over a pluralityof time periods.
 10. The method of claim 9 wherein said plurality oftime periods comprise time periods selected from the group consisting of15 seconds, 30 seconds, 1 minute, 2 minutes, 3 minutes, 5 minutes, 10minutes, 30 minutes, 1 hour, 3 hours, and 6 hours and 24 hours.
 11. Themethod of claim 1 wherein said step of determining a time rate of changeof body temperature comprises analyzing said time series of temperaturedata to determine a maximum time rate of change in a selected timeinterval within said at least one predetermined time periods.
 12. Themethod of claim 1 wherein said step of determining a time rate of changeof body temperature comprises determining the difference between thetemperature at the beginning of one of said at least one predeterminedtime periods and the temperature at the end of said one of said at leastone predetermined time periods, and dividing said difference by theduration of said one of said at least one predetermined time periods.13. The method of claim 1 wherein said step of determining a time rateof change of body temperature comprises determining the differencebetween the minimum temperature and the maximum temperature within oneof said at least one time periods and dividing said difference by thetime interval separating said minimum and said maximum temperatures. 14.The method of claim 1 wherein said threshold rate of change comprises apredetermined threshold rate of change.
 15. The method of claim 1wherein said threshold rate of change comprises a maximum rate oftemperature change associated with physical exercise by the patient. 16.The method of claim 1 further comprising the step of testing the patientwith an exercise test to determine a maximum rate of body temperaturechange over a predetermined exercise time period, and wherein saidmaximum rate of body temperature change comprises said threshold timerate of change.
 17. A method of determining a physiological marker foran epileptic seizure in a patient comprising: generating a first timeseries of temperature data representative of the body temperature of thepatient, determining when an epileptic seizure has occurred in thepatient, analyzing the time series temperature data for a predeterminedtime interval preceding the occurrence of the seizure to determine atleast one temperature marker in the data stream as a predictor of anepileptic seizure.
 18. The method of claim 17 further comprising thestep of storing said time series temperature data in a memory.
 19. Themethod of claim 17 wherein said step of determining at least onetemperature marker comprises determining a maximum rate of change oftemperature.
 20. A method of providing electrical neurostimulationtherapy to a cranial nerve of a patient comprising: generating a firsttime series of temperature data representative of the body temperatureof the patient; determining when an undesired physiological event hasoccurred in the patient; analyzing the first time series temperaturedata for a first predetermined time interval preceding the occurrence ofthe undesired physiological event to determine at least one temperaturemarker in the data stream as a predictor of the undesired physiologicalevent; generating a second time series of temperature datarepresentative of the body of the temperature of the patient; analyzingthe second time series temperature data stream for the presence of theat least one temperature marker; and providing an electricalneurostimulation therapy to said cranial nerve of the patient inresponse to detecting the presence of said at least one temperaturemarker in said second time series temperature data stream.
 21. Themethod of claim 20 wherein said step of providing an electricalneurostimulation therapy to the patient comprises changing a parameterof a previous neurostimulation program to be applied to the patient. 22.The method of claim 20 wherein said cranial nerve is selected from thegroup consisting of the vagus nerve, the trigeminal nerve, and theglossopharyngeal nerve.
 23. The method of claim 20 wherein said step ofgenerating a first time series of temperature data comprises sensingbody temperature of the patient with a temperature sensor at a desiredsensing rate.
 24. The method of claim 20 wherein said undesiredphysiological event is an epileptic seizure.
 25. The method of claim 21further comprising the steps of: generating at least a third time seriesof data representative of a physiological parameter selected from thegroup consisting of an action potential in a nerve tissue, a heartparameter, a blood parameter, and brain wave activity; analyzing thethird time series data for a second predetermined time intervalpreceding the occurrence of the physiological event to determine atleast a second marker in the third time series data stream as apredictor of the physiological event; generating a fourth time series ofdata representative of the selected physiological parameter; analyzingthe fourth time series temperature data stream for the presence of thesecond marker; and providing an electrical neurostimulation therapy tosaid cranial nerve of the patient in response to detecting the presenceof said second marker in the fourth time series data stream.
 26. Themethod of claim 25 wherein said electrical neurostimulation therapy isapplied to the patient only in response to the detection of both of saidtemperature marker and said second marker.
 27. A neurostimulator systemfor providing a neurostimulation therapy to a cranial nerve of a patientcomprising: a pulse generator capable of generating an electrical signalfor stimulation of a cranial nerve in a patient, a stimulation electrodeassembly coupled to said pulse generator and to said neural structurefor delivering said electrical signal to said neural structure, acontroller to regulate delivery of said electrical stimulation to saidneural structure, said controller comprising a temperature sensing unit,said temperature sensing unit comprising a temperature sensor element;timing circuitry, said circuitry operating to control the rate at whichsaid temperature element senses body temperature and to generate a firsttime series of temperature data preceding the occurrence of aphysiological event and a second time series of temperature data aftersaid event, temperature analysis circuitry, said circuitry operating toanalyze said first time series of temperature data to determine a markerof a physiological event, and said second time series of temperaturedata to detect the presence of said marker, and activation circuitry forcausing said pulse generator to provide said electrical signal to saidcranial nerve if said marker is detected in said second time series oftemperature data.
 28. The neurostimulator system of claim 27 whereinsaid cranial nerve comprises at least one nerve selected from the groupconsisting of a vagus nerve, a trigeminal nerve, and a glossopharyngealnerve.
 29. The neurostimulator system of claim 27 wherein said pulsegenerator is implanted in said patient and said stimulation electrodeassembly is coupled to said pulse generator by a lead assembly.
 30. Theneurostimulator system of claim 27 wherein said pulse generator isimplanted in said patient and said stimulation electrode assembly iscoupled to said pulse generator by a radio frequency transmitter andreceiver.
 31. The neurostimulator system of claim 27 wherein saidtemperature sensor comprises an implanted sensor coupled to said pulsegenerator by a lead assembly.
 32. The neurostimulator system of claim 27wherein said temperature sensor comprises a sensor that is part of anintegrated circuit chip.
 33. The neurostimulator system of claim 27wherein said controller comprises hardware and at least one of firmwareand software.
 34. The neurostimulator system of claim 27, wherein saidmarker comprises a time rate of temperature change exceeding a thresholdtime rate of temperature change.
 35. The neurostimulator of claim 34wherein said threshold time rate of temperature change comprises amaximum time rate of temperature change associated with physicalexercise by said patient.
 36. The neurostimulator of claim 27 whereinsaid marker comprises a difference in moving average temperature from afirst time domain to a second time domain.
 37. The neurostimulator ofclaim 27 wherein said first time domain comprises ten minutes and asecond time domain comprises two minutes.
 38. The neurostimulator ofclaim 27, further comprising a memory element for storing temperaturedata.
 39. A method of providing electrical neurostimulation therapy to acranial nerve of a patient comprising: generating a first time series oftemperature data representative of the body temperature of the patient,determining from the first time series of temperature data a bodytemperature parameter selected from the group consisting of a time rateof change of body temperature and a difference in a moving average bodytemperature for a first time domain and a moving average bodytemperature for a second time domain, comparing the body temperatureparameter to a threshold for the body temperature parameter, and if thebody temperature parameter exceeds said threshold, providing electricalneurostimulation pulses to a cranial nerve of the patient.
 40. Themethod of claim 39, wherein said step of providing electricalneurostimulation pulses comprises changing a parameter of an electricalneurostimulation therapy to be delivered to said cranial nerve.